Role of CYP3A4 in the regulation of the aryl hydrocarbon receptor by omeprazole sulphide

Cell Signal. 2006 May;18(5):740-50. doi: 10.1016/j.cellsig.2005.07.007. Epub 2005 Aug 16.


Cross-talk between nuclear receptors involved in the control of drug metabolism is being increasingly recognised as a source of drug side effects. Omeprazole is a well known activator of the aryl hydrocarbon receptor (AhR). We investigated the regulation of AhR by omeprazole-sulphide, a degradation metabolite of omeprazole, using CYP1A mRNA induction, reporter gene assay, receptor DNA binding, ligand binding, nuclear translocation, trypsin digests, and drug metabolism analysis in mouse Hepa-1c1c7, human HepG2 cells and primary human hepatocytes. Omeprazole-sulphide is a pure antagonist of AhR in Hepa-1c1c7 and HepG2 hepatoma cell lines. In Hepa-1c1c7 cells, omeprazole-sulphide is a ligand of AhR, inhibits AhR activation to a DNA-binding form, induces a specific pattern of AhR trypsin digestion and inhibits AhR nuclear translocation and subsequent degradation in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin. However, in highly differentiated primary human hepatocytes treated with rifampicin an agonist of the pregnane X receptor (PXR), omeprazole-sulphide behaves as an agonist of AhR. Inhibition of drug metabolizing enzymes by ketoconazole restores the antagonist effect of omeprazole-sulphide. Metabolic LC/MS analysis reveals that omeprazole-sulphide (AhR antagonist) is efficiently converted to omeprazole (AhR activator) by cytochrome P450 CYP3A4, a target gene of PXR, in primary human hepatocytes but not in hepatoma cells in which PXR is not expressed. This report provides the first evidence for a cross-talk between PXR/CYP3A4 and AhR. In addition, it clearly shows that conclusions drawn from experiments carried out in cell lines may lead to erroneous in vivo predictions in man.

MeSH terms

  • Active Transport, Cell Nucleus / physiology
  • Animals
  • Carcinoma, Hepatocellular
  • Cell Line, Tumor
  • Cells, Cultured
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism*
  • Genes, Reporter
  • Hepatocytes / cytology
  • Hepatocytes / metabolism
  • Humans
  • Liver Neoplasms
  • Mice
  • Omeprazole / analogs & derivatives*
  • Omeprazole / metabolism
  • Polychlorinated Dibenzodioxins / metabolism
  • Pregnane X Receptor
  • RNA, Messenger / metabolism
  • Receptors, Aryl Hydrocarbon / antagonists & inhibitors*
  • Receptors, Aryl Hydrocarbon / genetics
  • Receptors, Aryl Hydrocarbon / metabolism*
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Steroid / metabolism


  • Polychlorinated Dibenzodioxins
  • Pregnane X Receptor
  • RNA, Messenger
  • Receptors, Aryl Hydrocarbon
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Steroid
  • omeprazole sulfide
  • Cytochrome P-450 Enzyme System
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Omeprazole